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Publication numberUS4535157 A
Publication typeGrant
Application numberUS 06/547,676
Publication dateAug 13, 1985
Filing dateNov 1, 1983
Priority dateNov 1, 1983
Fee statusPaid
Also published asEP0140367A2, EP0140367A3
Publication number06547676, 547676, US 4535157 A, US 4535157A, US-A-4535157, US4535157 A, US4535157A
InventorsPeter C. Meltzer, Jotham W. Coe
Original AssigneeKey Pharmaceuticals, Inc.
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Reacting naloxone and naltrexone with potassium e-butoxide
US 4535157 A
Abstract
An improved Wittig reaction for making 6-desoxy-6-methylenenaloxone and 6-desoxy-6-methylenenaltrexone from naloxone and naltrexone utilizing an alkoxide base in an ethereal solvent.
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Claims(3)
What is claimed is:
1. A method of preparing a 6-desoxy-methylene compound of the formula ##STR1## wherein R is CH2 CH═CH2 or ##STR2## which comprises combining approximately equal molar amounts of potassium t-butoxide and methyltriphenylphosphonium formide to form a mixture and adding to that mixture tetrahydrofuran and stirring at about 20 C. for about 0.5 hours and then reacting with a compound of the formula ##STR3## at about 20 C. for about 40 minutes and stirring for about 1.25 hours and decomposing the reaction mixture by the addition of water in the presence of ammonium chloride and recovering the resultant 6-desoxy-6-methylene compound.
2. A method according to claim 1 wherein R is CH2 CH═CH2.
3. A method according to claim 1 wherein R is ##STR4##
Description

The present invention relates to an improved Wittig reaction for making 6-desoxy-6-methylenenaloxone and 6-desoxy-6-methylenenaltrexone (also called nalmefene) from naloxone and naltrexone, respectively.

Narcotic agonists such as morphine are commonly used to provide analgesia in cases of severe pain. As is well known, narcotic addiction and drug abuse are commonly associated with their use. Much effort has been directed to the development of satisfactory narcotic antagonists, drugs with the capacity to reverse or block the agonist effects of narcotics. Narcotic antagonists are presently used to reverse respiratory depression, a side effect when narcotics are administered, and are being tested as prophylactic agents in combating narcotic drug abuse. For the later purpose, a narcotic antagonist is required which exhibits little or no agonist properties, has an extended duration of action, and is preferably orally effective. Most narcotic antagonists synthesized thus far exhibit at least some degree of agonist activity.

The best known and currently utilized antagonists are naloxone and naltrexone; the later exhibits somewhat greater agonist activity but is of greater potency and has a longer duration of action. It has been discovered that the 6-desoxy derivatives of these compounds are even more useful as narcotic antagonists. Hahn and Fishman, J. Med. Chem., Vol. 18, No. 3, pp. 259-262 (1975) describe the preparation and properties of 6-desoxy-6-methylenenaloxone and 6-desoxy-6-methylenenaltrexone. The compounds were prepared on a small scale from naloxone and naltrexone, respectively, using preformed methylenetriphenylphosphorane, prepared in situ from methyltriphenylphosphonium bromide, sodium hydride and dimethyl sulfoxide, as the reagent, according to the method of Corey and Chaykovsky, J. Amer. Chem. Soc., 87, 1345, (1965).

The preparative process described by Hahn and Fishman requires complex temperature manipulations. For example, the dimsyl anion must be preformed at about 75-80 C., the reaction mixture cooled to room temperature, and the methyltriphenylphosphonium bromide added, followed by adding of Nalberone then brought to 55-60 C. for 18 hours, and cooled again for quenching. Attempts to scale up the Hahn and Fishman process, even on a modest scale, were unsuccessful.

We have discovered an improved process for the preparation of 6-desoxy-6-methylenenaloxone and 6-desoxy-6-methylenenaltrexone. Using an ethereal solvent and an alkoxide base to prepare the methylenetriphenylphosphorane reagent, only slightly in excess of three moles of methyl-triphenylphosphonium bromide is required, and not 60 moles as in the Hahn and Fishman process. Also, alkoxides are much easier and safer to handle than sodium hydride, making it feasible to carry out the reaction on a larger scale.

In general, the 6-desoxy-6-methylene derivatives are prepared, according to the invention, as follows: a vessel is charged with an alkoxide base, the alkali metal salt of a lower alcohol containing up to six carbon atoms, for example, potassium t-butoxide or potassium amylate and methyltriphenylphosphonium bromide. A lower-alkyl ether containing up to six carbon atoms such as tetrahydrofuran or diethyl ether, at 0-60 C., preferably 20-30 C., is introduced and the dispersion stirred. A solution of naloxone or naltrexone in the same ether at 0-60 C., again preferably at about room temperature is added with stirring. After stirring for a period of time to allow the reaction to go to completion, the reaction mixture is quenched with water or aqueous ammonium chloride at 0-50 C. and preferably 10-20 C. Decomposition with aqueous ammonium chloride is preferred because it is the most convenient approach to bringing the reaction mixture to the appropriate pH prior to extraction; otherwise base, such as ammonium hydroxide, need be added to bring the pH to 8. The resultant 6-desoxy-6-methylene compound is extracted with an organic solvent such as chloroform, purified by passage over silica, and crystallized from a suitable solvent in yields of about 90% of the theoretical. The free base so obtained can be converted to its acid addition salts in the usual manner; for example, hydrogen chloride in a solvent such as diethyl ether, tetrahydrofuran, methylene chloride, chloroform, or ethyl acetate gives the corresponding hydrochloride.

Our invention is further illustrated by the following non-limiting example.

A dry, 2-liter, 3-neck, round bottom flask fitted with two stoppers and a magnetic stirring bar was charged with potassium t-butoxide (61.1 g, 0.545 mol) and methyltriphenylphosphonium bromide (194.4 g, 0.544 mol). Freshly distilled tetrahydrofuran (450 ml) was introduced at 20 C. The resultant thick, bright yellow dispersion was stirred at 20 C. for 0.5 h and further dry tetrahydrofuran (100 ml) was added. A solution of dry naltrexone (60.0 g, 0.176 mol) in dry tetrahydrofuran (200 ml) was then added dropwise over 40 min to the well-stirred dispersion maintained at 20 C.

In another run using a similar procedure but only 30 g of naltrexone, the reaction mixture was stirred for a further 1.25 h, then cooled to 10 C., and quenched with 20% aqueous ammonium chloride solution (75 ml) followed by water (100 ml). The organic layer was separated and the aqueous layer extracted with four 100 ml portions of chloroform. Solvent was evaporated from the tetrahydrofuran layer and the combined chloroform extracts, the residues combined and brought to pH 2 by addition of 2N hydrochloric acid. The resultant precipitate was filtered, washed with chloroform (4100 ml) and suspended in a mixture of chloroform (500 ml) and water (250 ml). Ammonium hydroxide was added to attain a pH of 8 and the aqueous layer separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent removed in vacuo. The resultant solid was dissolved in ethyl acetate (1400 ml), the solution filtered through a silica pad and the solvent evaporated. The product was recrystallized from chloroform and washed with hexane to yield pure 6-desoxy-6-methylenenaltrexone as a white solid. Yield: 27.0 g, 88%.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3814768 *Nov 26, 1971Jun 4, 1974Lewenstein E6-methylene-6-desoxy dihydro morphine and codeine derivatives and pharmaceutically acceptable salts
US4322426 *Apr 28, 1980Mar 30, 1982E. I. Du Pont De Nemours And Company17-Substituted-6-desoxy-7,8-dihydro-6α-methylnoroxymorphone narcotic antagonists
Non-Patent Citations
Reference
1 *Hahn, et al., J. Med. Chem., vol. 18, No. 3, pp. 259 262 (1975).
2Hahn, et al., J. Med. Chem., vol. 18, No. 3, pp. 259-262 (1975).
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US5783583 *Apr 12, 1996Jul 21, 1998Simon; David LewNalmefene, withdrawal from drug dependence, side effect reduction
US5919760 *Jun 24, 1997Jul 6, 1999Intensive Narcotic Detoxification Centers Of America, LlcMethod for treating acute and severe diarrhea
US5922705 *Apr 13, 1998Jul 13, 1999Intensive Narcotic Detoxification Centers Of America, LlcRapid narcotic detoxification
US6087356 *May 25, 1999Jul 11, 2000Simon; David LewAnesthetizing the patient to produce a state of unconsciousness, administering dextromethorphan to reduce the feelings of withdrawal symptoms, administering an opioid antagonist to induce acute withdrawal
US6271240Sep 14, 1998Aug 7, 2001David Lew SimonProlonged, controlled administration of nalmefene, coadministered with bupropion, in steady state plasma concentration; achieved via sustained release delivery system (transdermal patch)
US7285665Nov 5, 2003Oct 23, 2007Mallinckrodt Inc.Process for the preparation of quaternary N-alkyl morphinan alkaloid salts
US7321038Oct 25, 2004Jan 22, 2008Mallinckrodt Inc.Method for the catalytic production of hydrocodone and hydromorphone
US7323565Nov 5, 2003Jan 29, 2008Mallinckrodt Inc.Using complex catalyst containing transition metal and phosphine
US7399858Mar 7, 2006Jul 15, 2008Mallinckrodt Inc.Method for the catalytic production of hydrocodone, hydromorphone, and derivatives thereof
US7736665Jun 2, 2003Jun 15, 2010Titan Pharmaceuticals, Inc.Implantable polymeric device for sustained release of buprenorphine
US8115002Sep 6, 2007Feb 14, 2012Mallinckrodt LlcPreparation of substituted morphinan-6-ones and salts and intermediates thereof
US8148528May 21, 2009Apr 3, 2012Mallinckrodt LlcProcesses and compounds for the preparation of normorphinans
US8598352May 21, 2010Dec 3, 2013H. Lundbeck A/SPreparation of nalmefene hydrochloride from naltrexone
US8669366Mar 6, 2008Mar 11, 2014Mallinckrodt LlcProcess for the preparation of quaternary N-alkyl morphinan alkaloid salts
EP2441766A1Dec 4, 2009Apr 18, 2012H. Lundbeck A/SNalmefene hydrochloride dihydrate
WO2010136039A1 *May 21, 2010Dec 2, 2010H. Lundbeck A/SPreparation of nalmefene hydrochloride from naltrexone
WO2012059103A1Nov 4, 2011May 10, 2012H. Lundbeck A/SMethod for the manufacturing of naltrexone
WO2013083685A1Dec 6, 2012Jun 13, 2013H. Lundbeck A/SProcess for recovery of nalmefene hydrochloride
WO2013164383A1May 2, 2013Nov 7, 2013H. Lundbeck A/SMethod for the manufacturing of naltrexone
Classifications
U.S. Classification546/44
International ClassificationA61P25/30, C07D489/08, A61K31/485
Cooperative ClassificationC07D489/08
European ClassificationC07D489/08
Legal Events
DateCodeEventDescription
Feb 11, 1997FPAYFee payment
Year of fee payment: 12
Oct 5, 1992ASAssignment
Owner name: BAKER NORTON PHARMACEUTICALS, INC., FLORIDA
Free format text: CHANGE OF NAME;ASSIGNOR:BAKER CUMMINS PHARMACEUTICALS, INC.;REEL/FRAME:006271/0501
Effective date: 19920722
Sep 24, 1992FPAYFee payment
Year of fee payment: 8
Aug 9, 1989ASAssignment
Owner name: BAKER CUMMINS LABORATORIES, INC.
Free format text: CHANGE OF NAME;ASSIGNOR:IVAX LABORTORIES, INC.;REEL/FRAME:005074/0070
Effective date: 19880811
Jan 23, 1989FPAYFee payment
Year of fee payment: 4
Dec 5, 1988ASAssignment
Owner name: BAKER CUMMINS PHARMACEUTICALS, INC.
Free format text: CHANGE OF NAME;ASSIGNOR:BAKER CUMMINS LABORATORIES, INC.,;REEL/FRAME:004983/0444
Effective date: 19881027
Owner name: BAKER CUMMINS PHARMACEUTICALS, INC., STATELESS
Dec 18, 1987ASAssignment
Owner name: IVAX LABORATORIES, INC., 8800 N.W. 36TH STREET, MI
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:KEY PHARMACEUTICALS, INC.;REEL/FRAME:004821/0705
Effective date: 19871120
Nov 1, 1983ASAssignment
Owner name: KEY PHARMACEUTICALS, INC. 18425 N.W. 2ND AVE., MIA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:MELTZER, PETER C.;COE, JOTHAM W.;REEL/FRAME:004191/0968
Effective date: 19831018